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In the fifty years since the discovery of JC polyomavirus (JCPyV), the body of research representing our collective knowledge on this virus has grown substantially. As the causative agent of progressive multifocal leukoencephalopathy (PML), an often fatal central nervous system disease, JCPyV remains enigmatic in its ability to live a dual lifestyle. In most individuals, JCPyV reproduces benignly in renal tissues, but in a subset of immunocompromised individuals, JCPyV undergoes rearrangement and begins lytic infection of the central nervous system, subsequently becoming highly debilitating—and in many cases, deadly. Understanding the mechanisms allowing this process to occur is vital to the development of new and more effective diagnosis and treatment options for those at risk of developing PML. Here, we discuss the current state of affairs with regards to JCPyV and PML; first summarizing the history of PML as a disease and then discussing current treatment options and the viral biology of JCPyV as we understand it. We highlight the foundational research published in recent years on PML and JCPyV and attempt to outline which next steps are most necessary to reduce the disease burden of PML in populations at risk.

BK virus (BKV) reactivation has been increasingly associated with the occurrence of late-onset hemorrhagic cystitis (HC) after allogeneic hematopoietic SCT (allo-HSCT) resulting in morbidity and sometimes mortality. We investigated the incidence, risk factors and outcome of BKV-HC in 323 consecutive adult patients undergoing allo-HSCT over a 5-year period. BK viremia values for HC staging were evaluated, as well as the medico-economic impact of the complication. Forty-three patients developed BKV-HC. In univariate analysis, young age ( P =0.028), unrelated donor ( P =0.0178), stem cell source ( P =0.0001), HLA mismatching ( P =0.0022) and BU in conditioning regimen ( P =0.01) were associated with a higher risk of developing BKV-HC. In multivariate analysis, patients receiving cord blood units (CBUs) ( P =0.0005) and peripheral blood stem cells ( P =0.011) represented high-risk subgroups for developing BKV-HC. BK viremia was directly correlated to HC severity ( P =0.011) with a 3 to 6-log peak being likely associated with grades 3 or 4 HC. No correlation was found between BKV-HC and acute graft versus host disease or mortality rate. Patients with BKV-HC required a significantly longer duration of hospitalization ( P <0.0001), more RBC ( P =0.0003) and platelet transfusions ( P <0.0001). Over the 5-year study period, the financial cost of the complication was evaluated at €2 376 076 ($3 088 899). Strategies to prevent the occurrence of late-onset BKV-HC after allo-HSCT are urgently needed, especially in CBU and peripheral blood stem cell recipients. BK viremia correlates with the severity of the disease. Prospective studies are required to test prophylactic approaches.

Widespread in the human population and able to persist asymptomatically for the life of an individual, polyomavirus infections cause a significant disease burden in the immunocompromised. Individuals undergoing immune suppression, such as kidney transplant patients or those treated for autoimmune diseases, are particularly at high risk for polyomavirus-associated diseases. Because no antiviral agent exists for treating polyomavirus infections, management of polyomavirus-associated diseases typically involves reducing or discontinuing immunomodulatory therapy. This can be perilous due to the risk of transplant rejection and the potential development of adverse immune reactions. Thus, there is a pressing need for the development of antivirals targeting polyomaviruses. Here, we investigate the effects of brincidofovir, an FDA-approved antiviral, on polyomavirus infection in vivo using mouse polyomavirus. We show that the drug is well-tolerated in mice, reduces infectious viral titers, and limits viral pathology, indicating the potential of brincidofovir as an anti-polyomavirus therapeutic.

Infection of immunocompromised individuals with normally benign opportunistic viruses is a major health burden globally. Infections with viruses such as Epstein-Barr virus (EBV), human cytomegalovirus (HCMV), Kaposi's sarcoma virus (KSHV), adenoviruses (AdV), BK virus (BKPyV), John Cunningham virus (JCPyV), and human papillomavirus (HPV) are significant concerns for the immunocompromised, including when these viruses exist as a co-infection with human immunodeficiency virus (HIV). These viral infections are more complicated in patients with a weakened immune system, and often manifest as malignancies resulting in significant morbidity and mortality. Vaccination is not an attractive option for these immune compromised individuals due to defects in their adaptive immune response. Verdinexor is part of a novel class of small molecules known as SINE (Selective Inhibitor of Nuclear Export) compounds. These small molecules demonstrate specificity for the nuclear export protein XPO1, to which they bind and block function, resulting in sequestration of XPO1-dependent proteins in the nucleus of the cell. In antiviral screening, verdinexor demonstrated varying levels of efficacy against all of the aforementioned viruses including previously with HIV. Studies by other labs have discussed likely mechanisms of action for verdinexor (ie. XPO1-dependence) against each virus. GLP toxicology studies suggest that anti-viral activity can be achieved at a tolerable dose range, based on the safety profile of a previous phase 1 clinical trial of verdinexor in healthy human volunteers. Taken together, these results indicate verdinexor has the potential to be a broad spectrum antiviral for immunocompromised subjects for which vaccination is a poor option.

Merkel Cell Carcinoma (MCC) is a rare and highly aggressive neuroendocrine skin cancer for which no effective treatment is available. MCC represents a human cancer with the best experimental evidence for a causal role of a polyoma virus. Large T antigens (LTA) encoded by polyoma viruses are oncoproteins, which are thought to require support of cellular heat shock protein 70 (HSP70) to exert their transforming activity. Here we evaluated the capability of MAL3-101, a synthetic HSP70 inhibitor, to limit proliferation and survival of various MCC cell lines. Remarkably, MAL3-101 treatment resulted in considerable apoptosis in 5 out of 7 MCC cell lines. While this effect was not associated with the viral status of the MCC cells, quantitative mRNA expression analysis of the known HSP70 isoforms revealed a significant correlation between MAL3-101 sensitivity and HSC70 expression, the most prominent isoform in all cell lines. Moreover, MAL3-101 also exhibited in vivo antitumor activity in an MCC xenograft model suggesting that this substance or related compounds are potential therapeutics for the treatment of MCC in the future.

ABSTRACT BK polyomavirus (BKPyV) affects 10%–30% of kidney‐transplant recipients receiving immunosuppressive therapy, potentially leading to nephropathy, graft dysfunction, graft loss, and increased mortality. Despite the medical need, no targeted therapies exist. This first‐in‐human trial evaluated the safety, tolerability, pharmacokinetics, and immunogenicity of potravitug, a novel fully human antibody against BKPyV. This partially randomized, single‐blinded, and placebo‐controlled trial enrolled 40 healthy participants randomized (3:1) to receive either single or multiple ascending doses (SAD/MAD) of potravitug or placebo intravenously. In the SAD phase, 16 participants were enrolled in 4 cohorts (n = 4 each) with escalating doses of 100, 500, 1000, and 2000 mg. In the MAD phase, 24 participants were enrolled in 3 consecutive cohorts (n = 8 each) with escalating doses of 500, 1000, and 2000 mg administered four times at four‐week intervals. The primary outcome was incidence, frequency, and severity of treatment‐emergent adverse events (TEAEs). Secondary outcomes included pharmacokinetic parameters and incidence of anti‐drug antibodies. The ex vivo neutralization capacity was an exploratory pharmacodynamic outcome. In SAD cohorts, 17 TEAEs occurred in 7 (58.3%) active and 3 in 2 (50.0%) placebo recipients. In MAD cohorts, 49 TEAEs occurred in 13 (72.2%) active and 21 in 5 (83.3%) placebo recipients. No dose‐limiting toxicities or anti‐drug antibodies were detected, indicating a favorable safety profile. Dose‐proportional increases in Cmax and AUC, with a half‐life characteristic of monoclonal antibodies, were observed. Based on pharmacokinetic‐pharmacodynamic modeling, a 1000 mg intravenous dose administered four times at four‐week intervals is expected to maintain sufficient drug concentrations and receptor occupancy of VP1 (BKPyV major capsid protein) in both the blood and kidney for at least 1 year.

BK virus is implicated in polyomavirus-associated nephropathy (PVAN) and hemorrhagic cystitis, particularly in kidney transplant recipients, affecting the functionality of the transplanted kidney and posing a risk of graft loss. Despite these challenges, specific antiviral drugs targeting BK virus remain elusive. Agnoprotein, a small, positively charged protein encoded by the BK virus late gene, functions in the assembly, maturation, and release of the virus. Consequently, agnoprotein emerges as a promising target for potential anti-BK virus drugs. Utilizing phage display technology, we conducted screening to identify specific binding peptides against the agnoprotein. The primary objective of screening binding peptides is to utilize them to disrupt the virus’s life cycle, impeding its replication and transmission, thereby achieving antiviral effects. In the current experimental study, a combination of phage 7 peptide libraries and 12 peptide libraries was employed for screening purposes. Following four rounds of screening, seven positive phages demonstrating the ability to bind Agnoprotein were successfully isolated. Following ELISA validation, it was observed that the optical density (OD) values for Agnoprotein binding of the seven positive clones significantly exceeded three times the value of the negative control (NC). Subsequent analysis identified one 7-peptide and six 12-peptides within the binding peptides. Moreover, OD values of dodecapeptide phage clones bound to agnoprotein were generally higher than those of heptapeptide phage clones.In conclusion, our study demonstrates the successful identification of specific binding peptides against agnoprotein, a crucial component in the BK virus life cycle.

The reactivation of BK polyomavirus (BKPyV) during severe immunosuppression plays a crucial role in two significant syndromes observed in transplant recipients: BK polyomavirus-associated nephropathy (BKPyVAN) in kidney transplant patients and BK polyomavirus-associated hemorrhagic cystitis (BKPyV-HC) in hematopoietic cell transplant (HCT) recipients. This review aims to summarize the current understanding and lingering ambiguity by looking at three primary questions: (1) In cases with BKPyV-related illnesses in transplant patients, which diagnostic methods have the best track record of accuracy and success? (2) Which therapy approaches have the best track records of safety and efficacy in real-world clinical settings? (3) What can immunological research teach us about the development of future tailored treatments? Diagnosis involves the patient’s appearance, ruling out other potential causes, and employing quantitative PCR to identify active viral replication in urine or plasma. BKPyV-HC can vary from self-limited hematuria to potentially fatal bleeding, while BKPyVAN may lead to loss and dysfunction of the allograft. Reducing immunosuppression remains the key aspect of treatment. However, the effectiveness of antivirals (such cidofovir and leflunomide) is not always the same, and supporting measures depend on the syndrome. Researchers are looking into new immunotherapies, such as virus-specific cytotoxic T cells. Due to the intricate viro-immunopathology and lack of defined treatment regimens, future initiatives should focus on prospective studies to establish validated thresholds, enhance management algorithms, and integrate immune surveillance into individualized therapy.

JC polyomavirus (JCPyV) infects the majority of the population and initially establishes a persistent but asymptomatic infection of the kidneys. In healthy individuals, the infection remains controlled by the host immune system, but for individuals experiencing prolonged immunosuppression, the infection can reactivate and spread to the brain, where it causes progressive multifocal leukoencephalopathy (PML), which is a fatal neurodegenerative disease. Currently, there are no approved therapies to treat PML, and affected individuals suffer rapid motor weakness and cognitive deterioration. To identify novel therapeutic treatments for JCPyV infection, receptor agonists/antagonists identified in a previously published drug screen were evaluated for their antiviral properties. Seven drugs were selected and validated using infectivity assays, and the mechanism of inhibition was further explored for G protein coupled receptor (GPCR)-associated inhibitors due to the role of the GPCR 5-hydroxytryptamine 2 receptors (5-HT2Rs) in JCPyV entry. The inhibitors cetirizine and paroxetine both reduced infection early in the JCPyV infectious cycle. Paroxetine specifically reduced viral internalization through altering the receptor density of 5-HT2CR, inhibiting β-arrestin recruitment to the receptor, and reducing MAPK signaling through ERK. These findings highlight the potential of receptor signaling and viral entry mechanisms as possible targets for antiviral drug development. Further, this research suggests that FDA-approved receptor agonists/antagonists currently used to treat other medical conditions could be repurposed into antivirals for the possible treatment of JCPyV infection and the fatal disease PML.

Background: In kidney transplant patients, polyomavirus-associated nephropathy (PVAN) represents a serious complication; the key factor for the development of PVAN is immunosuppression level and modulation of anti-rejection treatment represents the first line of intervention. Allograft biopsy and histology remain the criterion standard for diagnosing PVAN. Methods: All consecutive renal biopsies with the diagnosis of PVAN carried out at the University Hospital City of Health and Science of Turin over a five-years period were studied. Renal allograft biopsy was performed due to renal function alterations associated to medium-high polyomavirus BK (BKV)-DNA levels on plasma specimen. Results: A total of 21 patients underwent a first biopsy to diagnose a possible BKV nephropathy, in 18, a second biopsy was made, in eight, a third biopsy, and finally, three underwent the fourth renal biopsy; following the results of each biopsies, immunosuppressant agents dosages were modified in order to reduce the effect of PVAN. Conclusions: In this study, the clinical and histological features of 21 kidney transplant recipients with BKV reactivation and development of PVAN are described. To date, the only treatment for PVAN consists in the reduction of immunosuppressive agents, constantly monitoring viral load.